The purpose of this project is to determine the molecular basis underlying the genesis and progression of human malignant melanoma, and to identify novel genes associated with melanoma susceptibility in hereditary families. Melanoma has the fastest growing rate of incidence of any cancer in the Western world, and little is known about its molecular genetic changes. This project can be divided into four component parts. 1) Molecular analysis of tumor progression. [This focuses on clonal progression identified by tissue array technology, CGH, and on clonal karyotypic alterations in malignant melanoma]. 2) Identification of genes differentially expressed during growth, differentiation and progression. [This focuses on suppression of tumorigenicity of melanoma, cDNA subtraction/differential display, retroviral-mediated reversion of tumor suppression, and DNA microarray analysis of differential gene expression]. 3) Genomic analysis of chromosome alterations. [This involves cloning of chromosomal breakpoints in melanoma, using microdissection and other molecular biology approaches]. 4) Analysis of susceptibility loci in hereditary melanoma families using linkage analysis {This involves genotyping of families with non-p16 melanoma to identify loci, and ultimately cloning the genes conferring susceptibility to hereditary melanoma. A focus on WNT5A related to melanoma biology has been incorporated into this study and offers promising results.